The Half Decent Pharmaceutical Chemistry Blog

Finally, the quest for new mp3 to full my iPod with is over, for the moment. Thank you very much: I really appreciated and some of your songs/albums are great.

Strangely, none of you seem to think a scientist should have anything from Björk in the music library.
In particular, I find the last album of the mysterious Icelandic singer, with its evocative title, Medulla, simply staggering: I thought the idea of getting rid of all the instruments was stupid, but the result is dramatic.

The title, anyhow, made me realise there is a disease I've never properly studied, although its name marked most of last semester.
In fact, both pharmaceutical chemistry and pharmacology dealt with catecholamines and, indirectly, pheochromocytoma, believe it or not, has become a pretty familiar name.

This tumor arises in the adrenal medulla, an organ which synthesize a lot of epinephrine, so, you can imagine the consequences of a tumor in such a crucial area.

The most interesting thing about this pathology is that it can be perfectly described with the the so-called "rule of the 10%": in a case out of ten, in fact, both adrenal medullae are involved and figures indicate that 10% of pheocromocytomas arise in an organ other than the AM.



Hypertension is obviously the most common and severe outcome and the main cause of morbidity and mortality: that's why, although solely a tumor out of ten is malignant, a benign form requires prompt treatment.

Still, while it's easier to diagnose hypertension from one of its many, easy-to-assay hallmarks (high pressure, tachycardia, headache, sweating, etc.), suspiciously high levels of catecholamines in the urine reveal the origin of hypertension.

Last but not least, 10% of these cancers are associated with other diseases with very cool name, such as the von Hippel-Lindau, a rare type of neurocutaneous syndrome.

Even if whenever I came across this tumor it was in a description of drugs (namely, selective alpha-blockers), those substances are used for short periods: surgical excision remains the best way to deal with the problem.

So, today is April fool's day and many bloggers seem to be in the mood for jokes. Unfortunately, I don't like this particular day and believe someone, here in the hyperspace of the chemical blogsphere, has to take up the cross of writing incredibly eerie things on this very day. I like eerie stories.

Silica is something we all use: for instance, as a gel, it is a standard component of columns used for HPLC. Spectrophotometer cells are made of quartz, which is a crystalline form of silica.

Silica, however, is also associated with a pathology, silicosis, which is the major concern for sandblasters, quarry miners, etc.

Some figures from the WHO website: 9,000 diagnosed cases in Viet Nam, 300 deaths in the industrialized USA and more that 500,000 in China in the period between 1991 and 1995.

The cause of silicosis, however, is not silica per se, but crystalline one, which is also known to be fibrogenic. This is caused by its microscopic particles (5-1 µm), that easily reach the terminal airways.

Like all the most important diseases, there are different types of silicosis. Acute forms result from acute exposures to outrageously high quantities of silica dust, which lead to severe inflammations, cyanosis and respiratory failure.

A well-known feature of a chronic silicosis is the appearance of fibrotic nodules in the upper zones of the lung.



Interestingly, histological examination shows the presence of silica particles at the centre of the nodules.

As the disease proceeds, the nodules get larger than 2 cm and begin to coalesce. In the end, PMF (progressive massive fibrosis) will develop. And that is always the end...
At this point, although the exposition has ceased, hypoxia and fibrosis induce pulmonary hypertension, which progressively impairs pulmonary function.

This is a picture of Faenza, the capital of majolica and ceramic pottery.



It's a lovely town, not too far from where I live. The whole economy, there, is based on the production of world-famous, artigianal pottery.

So, you can imagine how the population reacted when, 10-years ago, the IARC put silica in its terrible Group 1: in that list of baddies, only substances which are undoubtedly carcinogenic to humans are listed.

Would you eat your pasta in a plate made of, say, Thorium? I sincerely doubt it.

Fortunately, the IARC kindly pointed out that only its crystalline form is actually carcinogenic.



That's why fibers of crystalline silica can break, yielding free valences, predictably extremely reactive and prone to yield free radicals when reacting with oxygen...that is rumoured to be pretty abundant in the alveoli...

 

These are some of the drugs used in the therapy against HIV.

They all work. Sort of.

However, they have dreadful toxicity and need to be taken in multi-drugs regimens, due to resistance and, in a nutshell, lack of power.

Some of them are rather amazing: efavirenz, for instance, and all the other non-nucleotide inhibitors have lovely structures.

The idea behind protease inhibitors is, in my opinion, brilliant (although they cause nasty adverse effects).

To sum up, these molecules are rather useful, but, somehow, they are...banal.
I mean, they don't have any feature which might eventually distinguish them among other antiviral. Nothing special which may make you fall in love with them, as I did with Imatinib.

And, besides, they were all designed in a rather predictable way: here is the virus, here are its enzymes...well, you know the rest, don't you?

If I studied medicine, I would probably like to become a microbiologist, in the end. And if I were a microbiologist (but, maybe, even as a pharmacologist can: who knows?), no doubt I'd focus on what is likely to be the least-known virus: HGV (hepatitis G virus).

You certainly heard of HBV and HCV, but I bet you never came across type G virus. Actually, this is no surprise: this RNA flavivirus is a relatively new (its discovery dates back to 1995) and has rather unusual characteristics.

In fact, it doesn't even cause a real disease. And it's not even hepatotropic, since its replication takes place in mononuclear cells.

Now, at this point, you might be thinking: "Why, the Hell, should anyone waste time on such a ridiculous virus, of which you can't even find a picture (or drawing) on the net?!"

Well, you would be wrong, because this could become the most important virus, ever! In particular, for what concerns HIV.

That's why the only, evident effect of HGV infection is dramatic reduction in the rate of replication of HIV. Not bad for a viral infection, eh?

To sum up, one of the least-known viruses seems to be an astonishing weapon against the most important of the viruses.

Not only did in vitro studies prove an inhibition in the replication of HIV in blood mononuclear cells, but similar findings resulted from experiments on HIV-infected patients.

Imagine this: you, mighty graduate student, choose a rubbish university, your PhD research project focuses on a virus no one cares about or even heard of and you end up finding a biochemical pathway (or some protein produced by HGV), which explains how this hepatovirus could inhibit the replication of HIV and leads to the development of a new, revolutionary class of drugs which can wipe out HIV infections and whose sole drawback is, say, somnolence!

Honestly, I can't think of anything better.